immune checkpoint inhibitors in thoracic...

Immune checkpoint inhibitors in thoracic malignancies

Rolf Stahel University Hospital Zürich Switzerland

Zürich 18.11.2015

ETOP | Name Project | Title Presentation | Zurich, July 27, 2009

Immune checkpoint inhibitors in thoracic malignancies

• Advanced NSCLC • Activity in pretreated patients • PD-L1 and other potential biomarkers • Activity in first line

• Earlier stages NSCLC • Consolidation after chemoradiotherapy • Adjuvant after section

• Small cell lung cancer • Mesotheliioma • Thymic carcinoma

2

Evolution of second line therapy for NSCLC: Key studies

3

Shepherd, JCO 2000

Docetaxel > BSC

Non-inferiority of pemetrexed to docetaxel

Hanna, JCO 2004

Erlotinib > placebo (2nd or 3rd line)

Shepherd, NEJM 2005

Docetaxel plus nintedanib (LUME-Lung-1) or docetaxel plus ramucirumab (REVEL) versus docetaxel plus placebo for second-line treatment of stage IV NSCLC: Overall survival benefit

4

LUME-Lung 1: Adenocarcinoma

OS 12.6 vs 10.3 ms OS 10.5 vs 9.1 ms

Reck, Lancet Oncol 2014; Garon, Lancet Oncol 2014

REVEL: 25% squamous cell carcinoma

Activity of immune checkpoint inhibitors in pretreated patients with advanced NSCLC

5

Nivolumab Pembrolizumab

Atezolizumab Durvalumab Avelumab

N 129 475 175 228 184RR

SCC Non-SCC

17% 18%

23.5% 19%

27% 21%

21% 13%

14%

Drug rel AE All grades Grade 3/4

41% 4.7%

71% 9.5%

66% 11%

50% 8%

77% 12%

RR PDL-1 + PDL-1 -

16% 13%

42% (>50%) 10% (<1%)

34% IC2/3 or TC 2/3

Gettinger S, J Clin Oncol 2015; 33: 2004-2012; Herbst R, Nature 2014; 515: 563-7; Soria JC, ESMO 2013; Garon E, NEJM 2015; 372: 2018-28;

Rizvi N, ASCO 2015; Guley LJ, ASCO 2015

Monotherapy with anti-PD1 nivolumab in second or later line NSCLC (phase I data)

6

Pts at Risk

Group Died/TreatedMedian OS, mo (95% CI) 1-year 2-year 3-year

9.2 (5.3, 11.1) 14.9 (7.3, 30.3) 9.2 (5.2, 12.4)

Months Since Initiation of Treatment

10090807060

0

5040302010

0 3 6 9 12 15 18 30 33272421 36 39 42 45 48 51 54 66636057

Censored

3-year OS = 27%2-year OS = 42%

Nivolumab 1 mg/kgNivolumab 3 mg/kgNivolumab 10 mg/kg

OS

(%)

33 (17, 49) 56 (38, 71) 38 (26, 50)

15 (5, 30) 42 (24, 58) 20 (11, 31)

15 (5, 30) 27 (12, 43) 14 (7, 25)

26/33 23/37 50/59

1 mg/kg 3 mg/kg 10 mg/kg

33 37 59

26 34 51

21 26 35

16 21 29

9 17 22

7 14 16

6 13 14

6 12 12

4 11 11

4 9 10

4 9 9

3 7 9

1 5 6

1 2 4

0 1 2

0 1 2

0 1 2

0 1 1

0 1 1

0 1 0

0 1 0

0 1 0

0 0 0

OS rate, % (95% CI)

Gettinger, Chicago 2014

• 54% pretreated with 3-5 therapies • 17% confirmed responses, 5% unconventional iR

Monotherapy with anti-PD1 pembrolizumab in second or later lane (phase 1 data)

7

• Pretreated pts. Same efficacy 2mg or 10mg/kg • Lower ORR in patients with liver metastases: 13.6% vs 21.2%

Hellman, WCLC 2015

Randomized phase II study comparing atezolizumab (vs docetaxel in 2L/3L NSCLC (POPLAR)

8

Vansteenkiste, ECCO-ESMO 2015

Median 12.6 mo (9.7, 16.4)

Median 9.7 mo (8.6, 12.0)

Minimum follow up = 13 months

HRa = 0.73 (0.53, 0.99) P value = 0.040

AtezolizumabDocetaxelCensored+

POPLAR: OS by PD-L1 Expression

0,1 1 10

In favor of docetaxel

0.73

1.04

0.59

0.54

0.49

Hazard Ratioa

In favor of atezolizumab

47 (16%)

105 (37%)

198 (68%)

92 (32%)

N = 287

0.2 1 2

Median OS (95% CI), moDocetaxel n = 143

7.4 (6.0, 12.5)

9.7 (8.6, 12.0)

9.7 (8.6, 12.0)

9.2 (7.3, 12.8)

11.1 (6.7, 14.4)

Atezolizumab n = 144

15.1 (8.4, NE)

12.6 (9.7, 16.4)

9.7 (6.7, 12.0)

15.5 (11.0, NE)

15.5 (9.8, NE)

n (%)

TC3 or IC3

TC2/3 or IC2/3

TC1/2/3 or IC1/2/3

TC0 and IC0

Subgroup

ITT

Vansteenkiste, ECCO-ESMO 2015

Effect of second line nivolumab on lung term surival: Confirmation of CheckMate 63

10

CheckMate 63:all histologies, 56% > 3rd line: 18-months OS rate 27%

CheckMate 17:SCC, 2nd line: 18-months OS rate 28%

CheckMate 57: Non-SCC, 2nd line: 18-months OS rate 38%

Horn, WCLC 2015

Second line therapy of squamous cell lung cancer: Comparisons accross recent studies

Nivolumab vs Doc:9.2 vs 6.0 months; HR 0.62 (0-48-0.81)

Pemetrexed vs Doc6.2 vs 7.4 months; HR 1.56 (0.8-2.26)

Docetaxel Ramucirumab vs Doc9.5 vs 8.2 months; HR 0.88 (0·69–1.13)

Docetaxel Nintedanib vs Doc8.6 vs 8.7 months; HR 1.01 (0.85-1.21)

Afatinib vs Erlotinib7.9 vs 6.8 months; HR 0.81 (0.69-0-95)

11

Reck, ECC0-ESMO 2015: Scaglotti Clin Lung Cancer 2010; Garon, Lancet Oncol 2014; Reck, Lancet Oncology 2014; Soria, Lancet Oncol 2015

Second line therapy of non-squamous cell lung cancer: Comparisons accross recent studies

Nivolumab vs Doc:12.2 vs 9.4 months; HR 0.73 (0-59-0.89)

Pemetrexed vs Doc9.3 vs 8.0 months; HR 0.78 (0.61-1.00)

Docetaxel Ramucirumab vs Doc11.1 vs 9.7 months; HR 0.83 (0.71–0.97)

Docetaxel Nintedanib vs Doc12.6 vs 10.3 months, HR 0.83 (0.7-0.99)

12

Horn, ECC0-ESMO 2015: Scaglotti Clin Lung Cancer 2010; Garon, Lancet Oncol 2014; Reck, Lancet Oncology 2014

Treatment effect on overall survival in predefined subsets 13

Borghaei. NEJM 2015

Phase III study of nivolumab versus docetaxel in second line non-squamous cell lung cancer (CheckMate-57): Overall survival

14

Nivolumab (n = 292)

Docetaxel (n = 290)

mOS, mo 12.2 9.4

HR = 0.73 (96% CI: 0.59, 0.89); P = 0.0015

Nivolumab

Docetaxel

1-yr OS rate = 51%

1-yr OS rate = 39%

292 232 194 169 146 123 62 32 09

290 244 194 150 111 88 34 10 05

Nivolumab

Docetaxel

Number of Patients at Risk

OS

(%)

Time (months)

100

90

80

70

60

50

40

30

10

0

20

27211815129630 24

Paz-Ares, ASCO 2015;

PD-L1 expression15

CheckMate 17 CheckMate 57 KEYNOTE 1

Pembrolizumab for the treatment of NSCLC: Prevalance of PD-L1 positivity and response according to PD-L1 positivity

16

Garon, AACR 2015

PD-L1 as a biomarker

PD-L1 IHC score

0

3

5

8

10

0 10 20 30 40 50 60 70 80 90 100

‘Negative’ ‘Positive’

Response?

Differential effects depend upon the Dose-response relationship

Courtesy Keith Kerr

Mutational landscape determines sensitivity of PD-1 blockade in NSCLC: Candidate neoantigens, response and PFS

18

Rizvi, Science 2015

15LBA: High tumoral IFNγ mRNA, PD-L1 protein, and combined IFNγ mRNA/PD-L1 protein expression associates with response to durvalumab (anti-PD-L1) monotherapy in NSCLC patients – Higgs B et al

• Key results – The ORR was 16% [32/300] (95%CI 11, 22) and pre-treatment PD-L1 status influenced

response: patients who were PD-L1 positive had an ORR of 27% [23/84] (95%CI 18, 38) compared with 5% [5/92] (95%CI 2, 12) for patients who were PD-L1 negative

– ORR by PD-L1 and IFNγ status is shown in the figure

Higgs et al. Ann Oncol 2015; 26 (suppl 6): abstr 15LBA

OR

R (%

)

0

25

50

75

100

31311

46

3327

PD-L1 +ve -ve +ve -ve +ve -ve

IFNγ -ve +ve +ve +ve -ve -ve

Prevalence 37% 35% 18% 19% 22% 41%

Less toxicity with immune checkpoint inhibitors in comparative studies

20

Toxicity Nivolumab squamous %

Docetaxel squamous %

Afatinib squamous %

Docetaxel / Ramucirumab %

All 59 87 93 98

Grade 3-4 8 58 57 79

Grade 5 0 2 2 5

Peters, WCLC 2015

CheckMate 57: Treatment-related adverse events21

Nivolumab (n = 287) Docetaxel (n = 268)Any Grade, % Grade 3–4,a % Any Grade, % Grade 3–4,a %

Total patients with an event 69 10 88 54Fatigue 16 1 29 5Nausea 12 1 26 1Decreased appetite 10 0 16 1Asthenia 10 <1 18 2Diarrhea 8 1 23 1Peripheral edema 3 0 10 <1Myalgia 2 <1 11 0Anemia 2 <1 20 3Alopecia <1 0 25 0Neutropenia <1 0 31 27Febrile neutropenia 0 0 10 10Leukopenia 0 0 10 8

Treatment-related adverse events reported in≥10% of patients

EQ-5D Utility Index:Mean Scores Over Time While on Treatment

22

Lung Cancer Norm (UK-based): 0.67b

Mea

n EQ

-5D

Util

ity In

dex

Scor

e

97 50 32 32 21 18 13 13 8Nivolumab (n = 97)

88 32 9 5 5 4 4 2 1Docetaxel (n = 89)

0 12 24 30 36 42 48 54 60

1.0

0.9

0.8

0.7

0.6

0.5

0.4

Population Norma

DocetaxelNivolumab

24

Higher scores indicate better health status. Only time points that had PRO data available for ≥5 patients in either treatment arm are plotted on the graph.

Week

Reck, ECCO-ESMO 2015

Pembrolizumab for the treatment of NSCLC: PD-L1 staining of tumor cells

23

Garon, AACR 2015; NEJM 2015

Pembrolizumab first line date (Keynote 001)24

Rizvi, ASCO 2015

Median PFS was6.1 months in all treated patients and 12.5 months with >50% PD-L1 staining

OS was not reached in all treated patients or in patients with ≥50% staining, and was 16.2 months and 10.4 months in patients with staining in 1%–49% and <1% of cells, respectively

BIRCH: Atezolizumab in TC2/3 and/or IC2/3 NSCLC25

0

10

20

30

3L+ 2L 1L

27%24%

26%

17% 17%19%

TC2/3 or IC2/3TC3 or IC3

OR

R, %

n = 65n = 139n = 267n = 253 n = 115 n = 122

• BIRCH met its primary endpoint in all predefined subgroups per protocol-specified criteria • Majority of responses were ongoing (> 61% in TC3 or IC3) • Median DOR was 7 mo in 3L+, NR in 1L/2L in TC3 or IC3, although follow-up is limited • IRF- and INV-assessed ORRs (per RECIST v1.1) were similar. In TC3 or IC3, eg, 27% vs 29% in

3L+; 24% vs 25% in 2L; and 26% vs 31% in 1L, respectivelyBesse, ECCO-ESMO 2015

Chemotherapy combination trials26

GP28328PhIb solid tumours (incl.

1L NSCLC) atezo + chemo (n=58)

KEYNOTE-021 PhI/II 1L NSCLC pembro + chemo

(n=49)

CheckMate 012PhI 1L NSCLC

nivo (N) + chemo (n=56)

CheckMate 012PhI 1L NSCLC nivo (N) + ipi (I)

(n=49)

Atezo + carbo/pac

Atezo + carbo/pem

Atezo + carbo/abrax

Pembro + carbo/pac

Pembro + carbo/pem

N10 + gem/cis

N10 + pem/cis

N10 + carbo/pac

N5 + carbo/pac

N1 q3w +I1 q3w

N1 q2w +I1 q6w

N3 q2w +

I1 q12w

N3 q2w +I1 q6w

n 8* 17* 16* 25 24 12 15 15 15 31 40 38 39

ORR, %

Grade 3–4 treatment-related AEs

69% 35% 45%

71% 54% 85% 32% 38% 25% 47% 73% 29% 29% 35% 29% 28%

0

25

50

75

100

50

77

56

28

58

3347 47 43

1325

39 31

Refs.

Camidge, et al.WCLC 2015

Giaccone, et al. ECC 2015

Papadimitrakopoulos, et al. ASCO 2015

Gettinger, et al. ESMO 2014

Rizvi, et al.WCLC 2015

Immunotherapy combination trial: CheckMate-12 ipilimumab and nivolumab. Treatment-related AEs

27

• There were no treatment-related deaths. Toxicities mailnly GI, hepatic, endocrine, skin, lung

Nivo 1 + Ipi 1 Q3W

(n = 31)

Nivo 1 Q2W + Ipi 1 Q6W

(n = 40)


(n = 38)


(n = 39)Nivo 3 Q2Wa

(n = 52)

Any Grade

Grade 3–4

Any Grade

Grade 3–4

Any Grade

Grade 3–4

Any Grade

Grade 3–4

Any Grade

Grade 3–4

Treatment-related AEs, % 77 29 73 35 74 29 69 28 71 19

Treatment-related AEs leading to discontinuation, % 13 10b 8 8c 5 3d 10 10e 10 10f

Nivolumab Median number of doses(range) Median duration of therapy, wks (range)

4(1–42) 12.0

(3.0–92.0)

7(1–26) 16.0

(2.0–59.0)

13(1–26) 28.7

(2.0–52.0)

8(1–25) 18.0

(2.0–53.0)

8(1–62) 16.0

(2.0–129.6)

Ipilimumab Median number of doses(range) Median duration of therapy, wks (range)

NC 1–4g

11.6(3.0–24.0)

3(1–9) 17.6

(6.0–59.0)

3(1–5) 35.7

(12.0–60.0)

2(1–9) 15.0

(6.0–54.0)

NA

NA

Immunotherapy combination trial: CheckMate-12 ipilimumab and nivolumab: Efficacy by PD-L1 expression

28

≥1% PD-L1 expression <1% PD-L1 expression

Nivo 1+ Ipi 1 Q3W

(n = 12)


(n = 21)

Nivo 3 Q2W

+ Ipi 1 Q12W

(n = 21)


(n = 23)

Nivo 1+ Ipi 1 Q3W

(n = 13)

Nivo 1 Q2W

+ Ipi 1 Q6W

(n = 7)

Nivo 3 Q2W + Ipi 1 Q12W (n = 9)


(n = 7)

ORR, % 8 24 48 48 15 14 22 0

mPFS, wks (95% CI)

11.5 (7.1, )

21.1 (11.4, )

34.6 (15.9, 35.3)

NR (15.4, )

34.0 (8.9, )

NR (10.1, )

23.1 (4.0, )

10.3 (7.4, 12.7)

PFS rate at 24 wks, % (95% CI)

42 (15, 67)

40 (18, 61)

74 (48, 88)

65 (42, 81)

57 (25, 80)

NC 39 (9, 69)

0

• All patients had available pretreatment tumor samples; 76% (113/148) had samples evaluable for PD-L1 expression • Median DOR was not reached in any arm, regardless of PD-L1 expression

Phase 3 anti PD1/PD-L1 Combination Trials in First-Line Advanced NSCLC

Durvalumab MYSTIC

Atezolizumab Impower 110

Ant

i-PD

-1/P

D-L

1

Nivolumab CHECKMATE 227

Primary endpoints: OS, PFS

Nivolumab

Nivolumab + ipilimumab

Platinum-based chemotherapy

Treatment-naïve or recurrent NSCLCN=1980

Atezolizumab

Gemcitabine + cisplatin or carboplatin

Primary endpoint: PFS

Stage IV squamous PD-L1+ NSCLC N=400

Atezolizumab + carboplatin + paclitaxel

Bevacizumab + paclitaxel + carboplatin

Primary endpoint: PFSAtezolizumab + bevacizumab + paclitaxel + carboplatinStage IV non-squamous NSCLC

N=1200

Atezolizumab + carboplatin + nab-paclitaxel

Carboplatin + nab-paclitaxel


Stage IV non-squamous NSCLCN=550

Atezolizumab

Carboplatin or carboplatin + pemetrexed

Primary endpoint: PFSStage IV non-squamous PD-L1+ NSCLC N=400

Atezolizumab + carboplatin + nab-paclitaxel

Carboplatin + nab-paclitaxel

Primary endpoint: PFSAtezolizumab + carboplatin + paclitaxel

Stage IV squamous NSCLCN=1200


Durvalumab

Durvalumab + tremelimumab

SOC chemotherapy

Advanced NSCLC N=675

Durvalumab NEPTUNE

Durvalumab + Tremelimumab

SOC chemotherapy

Primary endpoint: OS

First-line metastatic NSCLC N=800





Pembrolizumab KEYNOTE-189

Primary endpoints: PFS

Pembrolizumab + pemetrexed/platinum

Pemetrexed/platinum

Treatment-naïve non-squamous NSCLC N=580

Nivolumab CHECKMATE 026

Nivolumab 3 mg/kg IV Q2W

ICCa with potential for crossoverPrimary endpoint:

PFS

Treatment-naïve non-squamous NSCLC PD-L1–positive NSCLC

N=495

Pembrolizumab KEYNOTE-042

Pembrolizumab 200 mg IV Q3W

SOC chemotherapy

Treatment-naïve non-squamous NSCLC PD-L1–positive NSCLC

N=1240

Primary endpoint: OS

Peters, WCLC 2015

Immune checkpoint inhibitors in earlier stages of NSCLC treated with chemoradiotherapy

Consolidation after chemoradiotherapy

• NICOAS: A Feasibility Trial Evaluating Anti-PD1 Nivolumab Consolidation After Standard First-line Chemotherapy and Radiotherapy in Locally Advanced Stage IIIA/B NSCLC

• PACIFIC: A Phase III, Randomised, Double-blind, Placebo-controlled, Multi-centre, International Study of MEDI4736 as Sequential Therapy in Patients with Locally Advanced, Unresectable Non-Small Cell Lung Cancer (Stage III) Who Have Not Progressed Following Definitive, Platinum-based, Concurrent Chemoradiation Therapy

30

Immune checkpoint inhibitors after complete resection of NSCLC: PEARLS

31

SCLC: Nivolumab and nivolumab – ipiliumab combinations

32

SCLC (n = 128) with progressive disease after ≥1 prior line of therapy, including a platinum-based regimen in first line

(unselected by PD-L1 expression)

Nivolumab 3 mg/kg IV Q2W (n = 40)

Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg IV Q3W

for 4 cycles (n = 47)

aNivolumab 3 mg/kg + Ipilimumab 1 mg/kg IV Q3W


Nivolumab 1 mg/kg + Ipilimumab 1 mg/kg IV Q3W


Nivolumab 3 mg/kg IV Q2W

Primary objective: ORR per RECIST v1.1 Secondary objective: safety

Exploratory objectives: PFS, OS, biomarker analysis

Database lock: February 16, 2015

Antonia, ASCO 2015

SCLC: Nivolumab and nivolumab – ipiliumab combinations: Tumor responses and PD-L1 expression

33

Antonia, ASCO 2015

150

125

100

75

50

25

0

-25

-50

-75

-100

Bes

t Red

uctio

n fr

om B

asel

ine

in

Ta

rget

Les

ion

(%) <1% PD-L1

≥1% PD-L1Not evaluableb

Confirmed responders

Evaluable samples (40 of 90)

PD-L1 expression level, n (%)<1% ≥1%

Nivolumab (n = 22) 15 (68) 7 (32)Nivolumab + Ipilimumab (n = 18) 12 (67) 6 (33)

150

125

100

75

50

25

0

-25

-50

-75

-100

aCombined data for nivolumab 1 + ipilimumab 1 and nivolumab 1 + ipilimumab 3 cohorts. bNot evaluable due to specimens that are not quantifiable, indeterminate, or not yet obtained; 10 nonevaluable samples and 8 not yet obtained in the nivolumab arm, 6 nonevaluable samples and 26 not yet obtained in the nivolumab 1 + ipilimumab 3 arm. Only pts with target lesion at baseline and ≥1 on-treatment tumor assessment are included (nivolumab, n = 34, nivolumab + ipilimumab, n = 40).

Nivolumab + Ipilimumaba Nivolumab

SCLC: Pembrolizumab34

SCLC: Pembrolizumab (Keynote-28): PD-L1 expression

35

Ott, WCLC 2015

SCLC: Pembrolizumab (Keynote-28): Antitumor activity

36

Ott, WCLC 2015

SCLC: Pembrolizumab (Keynote-28): Change from baseline over time

37

Ott, WCLC 2015

ETOP / IFCT 4-12 STIMULI

STIMULI protocol amendment 138

• Treatment arminduction phase: nivolumab (1mg/kg i.v.) plus ipilimumab (3mg/kg i.v.), Q3W, 4 dosesmaintenance phase: nivolumab (240mg i.v.), Q2W, until PD for max 1 year

• Observation arm: best supportive careChemo-Radiotherapy:

cis-/carboplatin + etoposide 4 cycles

Biomaterial for translational research:

Consolidation vs observation:

induction maintenance

max 1 year

combination nivolumabnivolumab/ipilimumab

observation

Screening:

LD SCLC PCI

Tumourevaluation:

PD

off

Voluntary re-biopsy: → FFPE block

yes

noR

• • •

3 6 9 3 6 9 1812after randomisation

RT (Thoracic Radiotherapy): CT scans for tumour assessmentaccelerated schedule preferred - up to 18 months: every 9 weeksstart: day 1 of chemo cycle 1 or - up to 2 years: every 12 weeks

day 1 of chemo cycle 2 - years 3 & 4: every 6 months- at 5 years

0Week

Serum

At progression:

Whole blood Whole bloodWhole blood

RT

RT

from start of chemotherapy-2

CT

Serum SerumSerum

FDG-PET-CTor CT

Brain MRI or CT

Biopsy: FFPE block

or slides

27 ···

CT • • •

14 16

39

•Pleural plaques

Pleural plaques

Asbestosis

Pleural mesothelioma

Mesothelioma: Pembrolizumab (Keynote-28): PD-L1 screening

40

Alley, WCLC 2015

Mesothelioma: Pembrolizumab (Keynote-28): Antitumor activity

41

Alley, WCLC 2015

Mesothelioma: Pembrolizumab (Keynote-28): Antitumor activirty

42

Alley, WCLC 2015

Intensitiy and duration of therapy?A case of a 70-year old man with stage IV adenocarcinoma of the lung treated with two doses of atezolizumab

43

April 2014: Pretreatment

September 2014: After 2 doses of therapy in June

2014

March 2015: Hilar progression

T cell immune checkpoints as targets for immunotherapy

44

CTLA-4

PD-1

TIM-3

BTLA

VISTA

LAG-3HVEM

CD27

CD137

GITR

OX40

CD28

T Cell Stimulation

BlockingAntibodies

AgonisticAntibodies

InhibitoryReceptors

Activating Receptors

T cell

B7-1

T cell

In Phase 3 Studies

In Phase 1 Development

In Phase 1 Development

● Agonistic antibodies directed towards activating co-stimulatory molecules

● Blocking antibodies against co-inhibitory molecules may enhance T-cell stimulation to promote tumor destruction

immune checkpoint inhibitors in thoracic...

Documents